MXPA02007621A - Ocular hypotensive lipids. - Google Patents

Abstract

Compounds of formula (1), where the symbols are as defined in the specification, are useful as ocular hypotensive agents but do not exert their activity through the FP prostaglandin receptor. In particular the compound PGF2agr; 1 ethanolamide, having the formula (I) was discovered to be present in mammalian tissue as a naturally occuring substance, was synthesized in a substantially pure form and was found to be effective for lowering intraocular pressure in the mammalian eye, but not acting through the FP receptor through which many ocular hypotensive prostaglandins act.

Description

LIPID EYE HYPOTENSERS.

Field of the Invention The present invention relates to ocular hypotensive lipids. More particularly, the present invention relates to PGF-a 1-ethanolamide and related compounds, and to pharmaceutical compositions containing these compounds, as well as methods for using the compounds to reduce ocular pressure in a mammal. Brief Description of the Invention The prior art is well aware of numerous ocular hypotensive agents that are used to treat different ocular hypertensive conditions, including primary and secondary glaucoma, which represents a serious human health problem. Drugs used to treat ocular hypertension (glaucoma) include ß-adrenoreceptor antagonists, and different prostaglandins. There is a substantial volume of patent and scientific literature concerning prostaglandins and their use in the treatment of ocular hypertension. See for example Bito L.Z. Biological Protection wi th Prostaglandins Cohen, M.M. , ed. , Boca Ratón. Fia., CRC Press Inc., 1985, pp. 231-252; and Bito, L.Z., Applied Pharmacology in the Medical Treatment of Ref. 141129 Glaucomas Drance, S.M. and Neufeld, A.H. eds., New York, Grunt & Stratton, 1984, pp. 477-505. U.S. Patent No. 5,288,754 includes citations in addition to the specific prior art directed to prostaglandins and related derivatives, which are active as agents for reducing intraocular pressure in a mammal. U.S. Patent No. 5,288,754 likewise discloses "C-1 polar prostaglandin esters", which include C-1 amides and C-1 substituted amides of carboxylic acid compounds known as PGF2a. Additional prostaglandin derivatives related to PGF2a ge have emerged in the prior art research conducted in research facilities of the empowered corporation of the present application, and which also show strong intraocular hypotensive activity, are shown below by the formula and they are identified by arbitrary numbers as "number 1 prior art compound" and "number 2 prior art compound". The number 1 compound of the prior art is described in U.S. Patent Nos. 5,352,708; 5,607,978 and 5,688,819, and the number 2 compound of the prior art is described in U.S. Patent No. 5,545,665.

Composite of Previous Art no. 1 Composite of Previous Art no. 2 The vast majority of ocular hypotensive agents that have a structure related (or closely) to the prostaglandin, act through known "prostaglandin" receptors. Particularly, the compound PGF2a is known to exert its ocular hypotensive action through the receptor known as FP. By "FP receptor" is meant a human prostaglandin receptor as described in Abramovitz et al., J. Biol. Chem. 269-2632 (1994), incorporated herein by reference. The structure of PGF2a that includes the numbering regularly used in the nomenclature of prostaglandin and related compounds, is shown below.

PGF2ß The present invention is directed to a class of compounds related to PGF? A, 1-etanolap-ida that have surprisingly been discovered, together with compounds number 1 and 2 of the prior art, as agents having a strong ocular hypotensive activity , but do not exert their ocular hypotensive effects through the FP receptor, nor through any of these recognized prostaglandin receptors, such as DP, EP, EP2, EP3, EP4, FP, IP and TP. BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to the compounds of formula 1, wherein dotted lines represent the absence of a bond, or a bond provided that there are no two adjacent double bonds in the formula; the attached wavy lines represent either an alpha (a, below) or a beta (ß, above) configuration, where the wavy lines are attached to double bonds that represent either a Z (cis) or E (trans) configuration; the shaded lines indicate an alpha configuration (a) and the solid triangles indicate a beta (ß) configuration; m is an integer that has values from 0 to 5; n is an integer having the values 1-6, with the proviso that the compound represented by the formula is not PGF 2a 1-ethanolamide; q and r each independently, are integers that have the value of 0 to 6; X is CH2, O or S, with the proviso that when X is O or S, then the dotted lines adjacent to X represent the absence of a link; R is CH 3, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons or phenyl, furyl or thienyl, substituted by themselves with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons , N02, CN, COOH and COO alkyl, where alkyl has from 1 to 6 carbons; Ri, R2, R3, and R4 each independently represent H, a straight-chain alkanoyl group or branched chain having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons; R5 is H or a straight or branched chain alkyl group having 1 to 6 carbons, and R6 is H or a straight or branched chain alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of the compound, and the compounds are active to reduce intraocular pressure in the eye of a mammal, but do not exert their ocular hypotensive activity through the prostaglandin FP receptor, nor through any of the recognized prostaglandin receptors.

Formula 1 The present invention is also directed to a substantially pure isolated PGF2a-l-ethanolamide, which has surprisingly been discovered in certain biological systems as a naturally occurring substance. In addition, the present invention is directed to pharmaceutical compositions containing, as an active ingredient, PGF2 l-ethanolamide and / or one or more of the compounds according to formula 1, and to the process for treating a mammal, including a human, in need of such treatment, with an effective amount of a pharmaceutical composition containing PGF2a-l-ethanolamide as an active ingredient and / or one or more compounds according to formula 1, for the purposes of reducing intraocular pressure. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the effect of graduated doses of PGF2a-l-ethanolamide on the smooth muscle of the iris sphincter of a feline. The points are average values + _ SEM; n = 4 Figure 2 is a graph showing the inhibitory effect of graded doses of PGF2a-l-ethanolamide on contraction stimulated by a field of isolated vas deferens guinea pigs. The points are average values + • SEM; n = 4 Figure 3 is a graph showing the effect of graduated doses of PGF2a-l-ethanolamide on isolated chick ileum. The points are average values _ + SEM; n = 4 Figure 4 is a graph showing the effect of graded doses of PGF2a l-ethanolamide on isolated guinea pig ileus. The points are average values + SEM; n = 4 Figure 5 is a graph showing the effect of graded doses of PGF2a-l-ethanolamide on isolated rat aortic smooth muscle. The points are average values + SEM; n = 4 Figure 6 is a graph showing the increase in intracellular Ca2 + concentration [Ca2 +] i produced by graded doses of PGF2a (fl) and PGF2a l-ethanolamide () in CRL 1497 cells. The points are mean values + SEM; n = 4 Figure 7 is a graph showing the effects of the vasorelaxation of prostaglandin Fa l-ethanolamide, () And prostaglandin F2a (fl) in the rabbit jugular vein segment precontracted with histamine. The points are average values _ + SEM; n = 6 of PGF2a l-ethanolamide, n = 7 of PGF2a. Figure 8 is a graph showing the increase in intracellular Ca2 + concentration [Ca2 +] i produced by graded doses of PGF2a (fl) and PGF2a l-ethanolamide () in HEK-293 cells stably transfected with the feline FP recombinant receptor . The points are average values + SEM; n = 3 Figure 9 is a graph showing the accumulation of total inositol phosphate produced by graded doses of 17-phenyl prostaglandin F2a (A) and prostaglandin F2a l-ethanolamide (f) in HEK-293 cells stably transfected with the feline FP recombinant receptor. The values are means + - SEM. N = 3 Figure 10 is a graph showing the accumulation of total inositol phosphate produced by graded doses of 17-phenyl prostaglandin F2a (A) and prostaglandin F2a l-ethanolamide (f) in HEK-293 cells stably transfected with the recombinant FP receptor human . The values are means + SEM. n = 3 Figure 11 is a graph showing radioligand binding competence studies against 5 nM 3H-17-phenyl PGF2a with the use of HEK-293 cells stably transfected with the feline FP recombinant receptor. The competence provided by unlabeled PGFa-l-ethanolamide (f) and unlabeled 17-phenyl PGF2a (A) is described. The points are average values _ + SEM; n = 3 of the experiments performed in triplicate. Figure 12 is a graph showing radioligand binding competence studies against 5 nM 3H-17-phenyl PGF2a with the use of HEK-293 cells stably transfected with the recombinant human FP receptor. The competence provided by unlabeled PGF2a-l-ethanolamide (f) and 17-phenyl is described PGF2a not labeled (A). The points are average values _ + SEM; n = 3 of experiments performed in triplicate. Figure 13 is a graph showing the effect of 0.1% PGF2a-ethanolamide (f) on intraocular pressure of dogs. Contralateral vehicle received in the eyes (O) as control. The points are average values + SEM; n = 6 Figure 14 is a graph showing the effect of PGF2a l-ethanolamide at 0.1% (f) on the diameter of the dog's pupil. Contralateral vehicle received in the eyes (O) as control. The points are average values _ + SEM; n = 6 Figure 15 is a graph showing the effect of PGF2a l-ethanolamide (f) in ocular surface hyperemia of the dog. Contralateral vehicle received in the eyes (O) as control. The points are average values _ + SEM; n = 6 DETAILED DESCRIPTION OF THE INVENTION Surprisingly, it has been discovered in connection with the present invention, that PGF2a-l-ethanolamide is a naturally occurring substance, which can be formed from anandamide, a natural canabinomimetic, by COX-2 synthase and recombinant PGF. . It is known that COX-2 (cyclo-oxygenase-2) is an endoperoxide synthase of prostaglandin that is inducible and does not appear constitutively in tissues (see Meade et al., (1993) J. Biol. Chem. 268: 6610-6614). Since COX-2 is not expected to be present in unstimulated tissues, the discovery in connection with the present invention that substantial amounts of PGF2a ethanolamide are formed after administration of anandamide to wild type mice is unexpected. However, surprisingly, PGF2a ethanolamide is also detected in mice that received anandamide, suggesting that PGF2a ethanolamide is constitutive and that it can be conducted as an endogenously synthesized hormone. In accordance with the invention, PGF2a 1-ethanolamide is synthesized to provide this substance in an isolated and substantially pure form, to allow the formulation of pharmaceutical compositions containing this substance. The synthesis of PGF2a ethanolamide also allows the synthesis of all compounds within the scope of formula 1, only with such modifications in the synthetic process that are already available for the practice of organic chemistry, and particularly for the chemical practitioner in the field of prostaglandin and related chemistry. In this manner, the present invention encompasses the compounds of formula 1.

Preferred compounds within the scope of the invention are shown in formula la, and particularly preferred are compounds within the scope of formula la, wherein dotted lines between carbons 10 and 11, 8 and 12, and 17 and 18, they represent the absence of a link, and between carbons 5 and 6 represent a link. Furthermore, as far as the substitution of the hydroxyl functions of the compounds of the formula la or of the formula 1 (group Ri to R) is concerned, the compounds are currently preferred where one or more of the hydroxyl functions is not esterified or alkylated (one or more of Ri up to R 4 is H), or when the esterification of the esterifying group is alkanoyl having 1 to 6 carbons (formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, or any branched chain alkanoyl of 3 to 6 carbons). As regards the substitution designated R5 in the formula the o in the Formula 1, the compounds are preferred where R 5 is H or lower alkyl of 1 to 3 carbons, more preferably H. R 6 is preferably H or a lower alkyl of 1 to 3 carbons, more preferably H and n is preferably 2. With reference still to the formula and the formula 1, the configuration of the groups ORi, 0R2 and 0R3 is preferably alpha (C-9, C-11 and C-15 a), and the configuration of the double bond 5-6 is preferably Z (cis ). The most preferred compounds according to the present invention are PGF2a-l-ethanolamide and its asylated or alkylated derivatives, shown in formula 2, where Ri to R4 are defined in connection with formula 1, but asylated derivatives are more preferred than rented .

Formula 2 PGF2a l-ethanolamide = Rx = R2 = R3 = R4 = H The synthesis of the compounds of the invention is illustrated by the synthesis of the PGF2a-l-ethanolamide shown in Reaction Scheme 1, and also described below in experimental detail. Referring now to the reaction scheme, the commercially available triethanol amine salt (tromethamine) of the carboxylic acid PGF2a. it is treated with an acid to provide the free carboxylic acid. The free carboxylic acid PGF2a is converted to the methyl ester by treatment with a methylating agent (preferably methyl iodide) in the presence of an acid acceptor (preferably 1,8-diazabicyclo [5.4.0] undec-7-ene) to provide the methyl ester PGF2 - The methyl ester PGF2a is subsequently treated with ethanolamine to provide the PGF2a l-ethanolamide. In this manner, the entire "amide" portion is introduced into the molecule in the reaction between the methyl ester PGF2a and a hydroxyalkylamine derivative of the formula 3, wherein R5 and R6 and n are defined in connection with formula 1, and wherein the Formula 3 represents ethanolamine when R5, R6 are H and n is 2. The hydroxyalkylamines of formula 3 are available from the chemical literature and are within the skill of the practitioner of organic chemistry. The compounds where in formula 1 one or more of the dotted lines represent a bond, and / or where the configuration of the hydroxyl groups, or the configuration of the substituents around 1 or more double bonds is different than in the PGF2a l-ethanolamide, can be obtained by reactions analogous to those shown in the scheme of Reaction 1, however, starting with the C-1 carboxylic acid derivative of prostaglandin of the appropriate corresponding structure and stereochemistry. These starting compounds are available in accordance with the chemical literature, and are within the skill of the practitioner of organic chemistry. The compounds wherein in formula 1 one or more of the groups Ri to R is different from H, that is, compounds where one or more of C-9, C-11, C-15 and the hydroxyl group of the portion Hydroxyalkyl in the amide portion are esterified, or alkylated, can be obtained by esterification or alkylation reactions of the "free hydroxyl" compounds. Generally speaking, the modifications of the side chains and? of the compounds of formula 1 as defined in connection with the formula, are within the skill of the practitioner of synthetic organic chemistry in accordance with, or in analogy with, the disclosures in U.S. Patent Nos. 5,545,665; 5,834,498 and 5,352,708 the specifications of which they are expressly incorporated herein by reference. trametamine salt PGF 2] methyl ester PGF2 PGF2 1-ethanolamine s = H; R * - H; n = »2 Reaction Scheme 1 BIOLOGICAL ACTIVITY The compounds of the invention are unique in that they are potent ocular hypotensive agents that, however, do not act through the FP receptor. This is demonstrated in a number of assay procedures that are well accepted in the art for the stabilization of intraocular hypotensive activity, as well as for determining the receptor through which the compounds act. The ocular hypotensive activity of PGF2a 1-ethanolamide and its virtual inherence in a number of trials proving the activity of FP or other known prostaglandin receptors, are particularly striking and surprising when the biological profile of this compound is compared to the compound PGF2a "precursor". The description of the biological tests, and the results in the tests, is given below. METHODS STUDIES OF ISOLATED TISSUE The smooth muscle tension of isometrically isolated tissues was measured with force displacement transducers (Grass FT-03) and recorded in Grass polygraphs (model 7G and 79E). The organ lots contain Krebs solution maintained at 37 ° C and gasified with 95% 02/5% C02 to give a pH of 7.4. The Krebs solution has the following composition (mM): NaCl, 118.0; KCl, 4.7; KH2P04, 1.2; CaCl2, 1.9; MgSO4, 1.18; NaHCO 3, 25.0; glucose, 11.7; indomethacin, 0.001. (a) CAT IRIS Adult domestic cats were killed by an intravenous overdose of sodium pentobarbital (Anthony, Arcadia, CA). The eyes were immediately enucleated and placed on ice. The iris sphincter muscle was mounted vertically under 50 up 100 mg of tension in a 10 ml organ bath, chamfered. A stabilization period of 60 minutes was allowed before beginning each experiment. The activity was determined as contractile responses. The compounds were cumulatively added to the organ bath, and at least 30 minutes were allowed for recovery, after the wash was completed, and back to baseline tension. The response to PGF2a 10"7M was determined at the beginning and at the end of each experiment and between the dose response curves as a reference .. No more than two compounds were tested on each tissue, (b) RAT AORTA Sprague Dawley rats were anesthetized adults who weighed 180-220 grams per inhalation of C02, and then decapitated and bled to death.The thoracic aorta was removed and cleaned of any adhering tissue.The lumen was washed to remove any blood.The aorta was sectioned into three small segments 5-8 mm in length Each segment was mounted under 2 g of tension in a 10 ml organ bath enchaquetado with the help of two wire hooks placed through lumen of the container. This placement allowed the measurement of the contraction forces developed by the circular smooth muscle. The tissues were allowed to equilibrate for 1 hour before adding the compounds cumulatively to the organ baths. The responses to U-46619 10"7 M (a thromboxane mimetic) were determined at the beginning and at the end of each experiment as a reference, allowing a recovery period of 30-45 minutes after completing the drug wash. a test compound in each tissue, (c) CHICKEN ILEE Chick ileus is a preparation of the EP3 receptor.Portions of chick ileus of 1.5 cm in length were suspended under 1 g of tension.After a period of equilibration of 1 hour, a standard dose response curve for PGE2 is obtained in a non-cumulative manner, with periods of 30 minutes of washing between individual doses, and then the test compound is added non-cumulatively. PGE2 (10 ~ 6 M) to serve as a second standard reference The contractile activity in each concentration is then calculated as a percentage of the maximum PGE2 response reached at a concentration of 10"6 M. (d) ISLE OF INDIAN CONEJILLO The guinea pig ileus is a preparation of the EPX receptor. A segment of approximately 1.5 cm of guinea pig ileus was suspended in a caged organ bath under 1 g of tension. After an equilibrium period of 1 hour, the response curve to the wash dose for PGE2 is obtained. Periods of 30 minutes of washing are allowed between doses. A dose response curve for PGF2a l-ethanolamide is then generated identically. A final administration of PGE2 10"6 M is given as reference. The data are expressed as the maximum percentage of the PGE2 response. (E) DEFERRING CONDUIT OF THE INDIAN CONEJILLO The activity in the subtype of the prostaglandin-sensitive EP3 receptor is also Determined by the ability of prostanoids to inhibit the pull response of smooth muscle stimulated by an electrical current in the deferent conduit isolated from guinea pigs.Deferent conduits of the guinea pig were suspended in 1.5 cm portions under an initial tension of 1 g, and they were allowed to equilibrate for at least 30 minutes.The tissues were then subjected to a stimulation every 30 seconds by electric pulses of 20 volts.After the stabilization of the response to the pull, a standard dose response curve for PGE was performed cumulatively. The test compounds were then evaluated to perform a cumulative dose response curve. The fabrics were washed and allowed to equilibrate for 1 hour between the compounds. The PGE2 was once again evaluated at the conclusion of the experiment as a standard reference. The activity was calculated as the percentage of inhibition of the height of the muscle pull response. (f) YUGULAR RABBIT VENUE New Zealand albino rabbits of both sexes were injected, weighing 2-4 kg, with 1000 U of heparin in the marginal ear vein, and then sacrificed by C02 gas. The external jugular veins of fat and adherent connective tissue were cleaned and removed. The veins were cut transversely and each ring of 3-4 mm in length was suspended between two metal hooks in a slatted organ bath. The tissues were equilibrated for 1 hour under 0.75 g of tension, which was re-adjusted as the tissue was relaxed. Simple doses of histamine were given 10"5 M, then 2-3 x 10 ~ 6 M, with washing after each dose, to contract the tissue and stabilize the responses.The SQ29548 antagonist of the TP receptor was applied (Ogletree et al. (1985) J. Pharmacol. Exp. Ther. 234 435-441) a (10 ~ 6 M), for 5 minutes, and then 2-3 histamine was added per 10"6 M to elicit the contractile response.After 30 minutes of pretreatment with histamine, the relaxant response was tested by adding cumulative doses of the test compounds with PGE210" 8 M to 10 ~ 7 M at the end of each dose response curve as a reference. A recovery period of 30-50 minutes after washing the tissues was allowed. Relaxant activity was calculated as the percentage of the control tone produced by histamine. (g) HUMAN PLATELETS The activity of the prostanoid in the DP-, TP- and IP- receptor types was determined by the ability to cause aggregation (TP receptor activity) or to inhibit the ADP-induced aggregation of human platelets in vitro ( activity of the receiver DP- and IP-). Fresh whole blood is obtained from healthy human volunteers with consent, and mixed with dextrose-acid citrate (ACD). The blood is centrifuged at 1000 rpm for 15-20 minutes to obtain a platelet-rich plasma (PRP). 4.5 μl of prostanoid or vehicle is added to 450 μl of PRP and incubated for 2 minutes at 37 ° C in a Payton aggregometer, and observed for any aggregative activity. ADP is then added 2 x 10"5 M (final concentration) to induce aggregation complete The inhibition of aggregation is calculated as the percentage of difference between the aggregation evoked by ADP 2 x 10"5 M in the absence and presence of the drug The aggregation activity is calculated as the percentage of aggregation induced by the prostanoid in relation to the aggregation induced by ADP 2 x 10"5 M. Standard aggregatory responses are made for ADP 2 x 10" M only at the beginning and end of each experiment, (h) CRL CELLS 1497: SIGNAL Ca2 + Human CRL 1497 cells were seeded in flasks of were cultured and fed a Dulbecco modified Eagle medium (DMEM) containing 10% fetal calf serum, 2 mM l-glutamine, and 0.05 mg / ml gentacin (all purchased from Gibco, Grand Island, NY). Cells are kept in a humidified atmosphere of 95% air, 5% C02 and grow to confluence.The cells of the culture flasks are removed by treatment of approximately 1 minute with 0.05% trypsin / 0.53 mM EDTA in a solution. Hanks balanced salt ion (HBSS, Gibco, Grand Island, NY) at 37 ° C. Proteolytic activity is interrupted by adding 5 ml of 10% fetal bovine serum in DMEM. The cells are washed consecutively in Hank's BSS medium containing 140 mM NaCl, 50 mM KCl, 1 mM MgCl 2, 1.5 mM CaCl 2, 10 mM HEPES: TRIS, 5 mM glucose, 5 mM Na pyruvate, 0.1% bovine serum albumin at pH 7.4: Centrifugation for washing is carried out for 15 minutes at 200 g at room temperature. The cells are counted, resuspended in the above medium and incubated with Fura 2/2 x 10"6 M acetoxymethyl ester in a stirred water bath for 30 minutes at 37 ° C. The cells are subsequently washed in a medium as above, and resuspend at a concentration of 2 x 10 6 i-1 cells, then aliquots of 0.5 ml of cell suspension are added to the self-tapping icrotubes to provide 10 cells by experimental determination of free Ca 2+ intracellular concentration. ([Ca2 +]. The fluorescence was measured in a Perkin-Elmer LS-5 fluorescent spectrophotometer at excitation and emission wavelengths of 340 and 492 nm, respectively, both with openings at 10 nm For each experimental determination, 106 were washed. cells (200 xg for 5 minutes) and suspended in a 2 ml cuvette with buffer containing 120 mM NaCl, 6 mM KCl, 1 mm MgSO 4, 1.5 mM CaCl 2, 20 mM HEPES, 1 mg ml 1 glucose and 1 ml. mg ml-1 of pyruvate Na. agitation was performed by a stirring paddle, mounted on the top, with the temperature maintained at 37 ° C. The cells were used with digitonin (10 μl of 100 mg ml-1 DMSO) to obtain fmax-EGTA (100 M) and then added successively enough ION NaOH to adjust the pH to 8.5, to obtain Fp.n- • (i) RECOMBINANT CAT AND HUMAN RECEPTOR; STABLE TRANSFECTORS. HEK-293 cells were grown in DMEM with 10% fetal bovine serum (FBS), 250 μg ml-1 G418 (Life Technologies) and 200 μg ml-1 gentamicin or penicillin / streptomycin. The selection of stable transfectants was performed with 200 μg ml-1 of hygromycin, the optimal concentration is determined by hygromycin elimination curve studies. For transfection, the cells were grown to a confluence of 50-60% in 10 cm plates. Plasmid pCEP4 incorporating inserted cDNA for the human FP receptor (20 μg) was added to 500 μl of 250 mM CaCl2. HEPES x 2 buffered saline (2 x HBSS, 280 mM NaCl, 20 mM HEPES acid, 1.5 mM NaHP04, pH 7.05-7.12) was then added dropwise to a total of 500 μl, with continuous vortices at room temperature. After 30 minutes, 9 ml of DMEM was added to the mixture. The DNA / DMEM / calcium phosphate mixture was then added to the cells, which were previously rinsed with 10 ml of phosphate buffered saline.

(PBS). The cells were incubated for 5 hours at 37 ° C in 95% humidified air / 5% C02. The solution of Calcium phosphate was then removed and the cells were treated with 10% glycerol in DMEM for 2 minutes. The glycerol solution was replaced by DMEM with 10% fetal bovine serum (FBS). The cells were incubated overnight, and the medium was replaced by DMEM / 10% FBS containing 250 μl ml "1 of G418 and penicillin / streptomycin The next day, hygromycin B was added to a final concentration of 200 μg ml " Ten days after transfection, the hygromycin B resistant clones were individually selected and transfected into a separate well in a 24-well plate. At the confluence, each clone was transfected into a well of a 6 well plate, and then expanded into a 10 cm dish. The cells are kept under continuous hygromycin selection until used. The stable transfectants of the cat FP receptor were prepared in a similar manner with the use of lipofectamine. The cells are again grown to a confluence of 50-60% in 10 cm plates, and the plasmid pCEP4, which incorporates inserted cDNA for the • Phenyl FP receptor, is transferred with the use of lipofectin. The selection of hygromycin B is started 48 hours after transfection. Eight days after the transfection, the hygromycin B resistant clones are selected and transferred to 24-well plates. The Ca2 + signaling studies in the recombinant cat and human FP receptors are performed in a manner identical to that described for the CRL 1497 cell studies. (J) FORMATION OF INOSITOL PHOSPHATE The hydrolysis of phosphoinositide (Pl) was determined. ) mediated by the receptor, by measuring the accumulation of total inositol (PI) phosphates in cells previously incubated with 3H-myoinositol. Stable cell lines of HEK 293 cells expressing the FP receptors of human or cat were planted in 10 cm dishes (106 cells per dish in DMEM with 10% FBS). The next day, the cells were incubated with 18 μCui myo- [2 3 H] inositol (Amersham, 10-20 μCi mmol "1) in 6 ml of DMEM with 10% FBS for 24 hours at 37 ° C. The cells were then rinsed twice with phosphate buffered saline (PBS), incubated for 5 minutes with 1 ml of trypsin-EDTA, and suspended in 10 ml of DMEM containing 25 mM of HEPES buffer. The cells were pelleted at 1000 rpm and resuspended in DMEM / 25 mM HEPES containing 10 mM LiCl for 10 minutes. Aliquots of 200 μl of cell suspension were incubated with 50 μl of drug for 30 minutes at 37 ° C (determination in duplicate), and the agonist stimulation was terminated with a mixture of 750 μl of chloroform: methanol: 4N HCl (100: 200: 2), followed by the addition of 250 μl of chloroform and 0.5 N HCl for the extraction of the inositol phosphates. A volume of 750 μl of the aqueous layer was loaded onto columns packed with 0.5 ml of Dowex AG 1-X8 anion exchange resin (formate form, 100-200 mesh); BioRad) to separate the radiolabel components. The elution procedure consists of three 3 ml washes with 5 mM inositol, then two elutions with 750 μl of 1.3M ammonium formate with 0.1M formic acid. the eluate was mixed with 10 ml of Aquasol scintillation fluid (Packard Instrument Co.) and the total phosphate of [3H] inositol was determined by a liquid scintillation counter, (k) RADIOLIGANDO LINK Membrane preparations are obtained as follows of plasma of HEK 293 cells stably transfected with the FP receptor of human or feline. The cells washed with TME buffer are scraped from the bottom of the flasks and homogenized for 30 seconds with the use of Brinkman PT 10/35. the TME buffer solution is added as necessary to reach a volume of 40 ml in the centrifuge tubes. The TME it comprises 100 mM TRIS base, 20 mM MgCl 2, 2 m EDTA; a physiological pH is reached by adding 10 N HCl. The cell homogenate is centrifuged at 19,000 rpm for 20 minutes at 4-6 ° C with the use of a Beckman Ti-60 rotor. The pellet is then resuspended in TME buffer to provide a final protein concentration of 1 mg / ml, as determined by the Biorad assay. The radioligand binding assays are performed in a volume of 200 μl. The binding of [3H] (N) 17-phenyl PGF2a (specific activity 85 Ci / mmol) was determined in duplicate, and the experiments are replicated three times. Incubations were for 60 minutes at 25 ° C, and were terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl, followed by rapid filtration through filters Whatman GF / B and three additional washes of 4 ml in a cell harvester (Brandel). The end of the studies was carried out with the use of a final concentration of [3 H] (N) 17 n-phenyl PGF2a 5 nM, and a non-specific binding was determined with unlabeled 10"5 phenyl PGF2a. (1) INTRAOCULAR PRESSURE (IOP) Intraocular pressure studies in dogs involve performing the pneumatonometry in Beagle dogs, conscious, of both sexes (10-15 kg) .The animals are conscious during the study, and they are retained gently with your hand The drugs were administered topically to one eye as a drop of 25 μL volume, the other eye receives 25 μL of the vehicle (0.1% polysorbate 80: 10 mM TRIS) as control. Proparacaine 0.1% is used for corneal anesthesia during tonometry. The infraocular pressure is determined just before drug administration and at 2, 4 and 6 hours later on each day of the 5-day study. The drug is administered immediately after the first IOP reading. (m) DIAMETER OF PUPILA. The diameter of a dog's pupil was measured with the use of an "optistick" (a ruler in mm that includes half-circle references of standard widths (mm) for reference). Holding the dog gently by hand, the diameter of the pupil is determined by marking a half circle in the pupil under normal ambient light. In dogs with very dark pupils, a specialized light pen was used, but only very briefly to avoid constriction of the pupil. The diameter of the pupil was measured at the same time as the IOP and hyperemia, (n) EYE SURFACE HYPERTHEMIA. Eye surface hyperemia was visually evaluated and recorded in accordance with a typical clinically used system.

Assigned Hyperremia Valuer Marker < 1 trace 0.5 1 mild 1 moderate 2 severe 3 Ocular surface hyperemia was evaluated at points at the same time as the measurement of intraocular pressure. It will be noted that the eyes of untreated dogs often have a pink / red tone. In this way, trace or even moderate values are not necessarily outside the normal range. Results The effects of prostaglandin F2a-l-ethanolamide on the feline iris sphincter are described in Figure 1 and tabulated (Table 1). Prostaglandin F2a 1-ethanolamide (PGF2a-l-ethanolamide) produces a dose-dependent contraction of the smooth muscle of the cat iris sphincter. A value (E.C.) 50 of effective concentration of 58 nM is obtained. The data indicate a concentration threshold in the region of 10 nM. Prostaglandin F2a-l-ethanolamide was modestly effective in inhibiting the field stimulation of the contraction evoked from the guinea-pig preparation deferent isolate. The data are described in Figure 2 and tabulated (Table 2).

Figure 3 describes the effect of PGF2a 1-ethanolamide on isolated chick ileus. The comparison of responses to the reference compound (prostaglandin E2, 10"and M) suggests that PGF2a-l-ethanolamide may behave as a weak partial agonist.The data are listed in Table 3. PGF2a-l-ethanolamide appears less effective in the guinea pig ileus (Figure 4; Table 4), which is reported to be a preparation of the EPX receiver. The effects of graded doses of PGF2a-l-ethanolamide on the isolated rat aorta are shown in Figure 5 and Table 5. Residual activity occurs at high doses, 10"6 and 10 ~ 5 M. Since the aorta of rat is a TP receptor preparation, the TP receptor activity is further evaluated in terms of platelet aggregation.In addition, the inhibition of human platelet aggregation induced by ADP, was determined to reveal any interaction in the DP or IP receptors The effects on the platelets were not apparent The data are presented in Table 6. A graph is not provided since absolutely no response occurs The Ca2 + signal produced by graduated doses of prostaglandin F2a l-ethanolamide in human dermal fibroblasts CRL cells 1497) is compared with the produced by prostaglandin F2a in Figure 6. The data are also tabulated (Table 7). The E.C.sub.50 values obtained are 16 nM for PGF2a and 1586 nM for PGF2a l-ethanolamide, which indicate about a hundredfold difference in potency in the human FP receptor. Recent studies show that prostaglandin F2a can produce vasorelaxation mediated by nitric oxide (NO), dependent on the endothelium, (Chen et al., (1995) Br. J. Pharmacol, 116: 3035-3041). In this way, the effects of PGFa-l-ethanolamide are compared with those of PGF2a in the production of the endothelium-dependent vasorelaxation of the isolated rabbit jugular vein segment, precontracted with histamine. Although PGF2a potentially produces a marked vasorelaxation, PGF2a l-ethanolamide exhibits relatively little activity (Figure 7). The data are also tabulated (Table 8). The following E.C. are obtained from the vasorelaxation of the segment of the jugular vein of rabbit precontraída: PGF2a 1-ethanolamide = 2000 nM, PGF2a = 5.3. Since a marked activity is observed for PGF2a-l-ethanolamide in the cat iris sphincter preparation, its activity is compared to that of PGF2a in the FP feline recombinant receptor. Figure 8 compares the activity of PGF2a-l-ethanolamide and PGF2a in obtaining a Ca2 + signal in HEK-293 cells stably transfected with the recombinant feline FP receptor. The E.C50 values of 14 nM for PGF2a and 1458 for PGF2a l-ethanolamide are obtained, indicating an approximately 100-fold difference in potency. The data is also tabulated (Table 9). The effects of PGF2a-l-ethanolamide and 17-phenyl PGF2a on the total accumulation of inositol phosphate in HEK-293 cells stably transfected with the recombinant phenyl FP receptor are described in Figure 9. Again, a separation is apparent great in power. The E.C50 values are 9 nM for 17-phenyl PGF2a and 524 nM for PGF2a l-ethanolamide. The data is tabulated (Table 10). In addition, the effects of PGF2a 1-ethanolamide and 17-phenylPGFa on the total accumulation of inositol phosphate in HEK-293 cells stably transfected with the human recombinant FP receptor are examined. The E.C50 values of 8 nM are obtained for 17-phenyl PGF2a and 1003 nM. The data are presented in Figure 10 and Table 11. The results are similar to those obtained by the feline recombinant FP receptor.

Consistent with functional studies employing stably transfected FP receptor preparations, PGFa l-ethanolamide has a relatively modest binding affinity for the FP receptor. Thus, PGF2a-l-ethanolamide (compound of the prior art No. 1) has only a weak affinity for the phenyl receptor, while 17-phenyl PGF2a exhibits a high affinity (Figure 11, Table 12). The inhibitory concentration50 (I.C.50) for the obtained PGF2a-l-ethanolamide was 882 nM, compared to a I.C.50 value of 43.5 nM for 17-phenyl PGF2a. Similar results are obtained for the human recombinant FP receptor: PGF2a l-ethanolamide I.C.S0 = 2015 nM, 17-phenyl PGF2aI. C.50 = 2.3 nM. These radioligand binding data are described in Figure 12 and tabulated (Table 13). The ocular effects of PGF2a-l-ethanolamide are studied in dogs. PGF2a l-ethanolamide at a 0.1% dose produces a marked and highly significant reduction in intraocular pressure (Figure 13, Table 14). The effect persists during the entire experimental period of 24 hours. PGF2a-l-ethanolamide also causes marked miosis (Figure 14, Table 15). Contrary to the ocular hypotensive effect, the reduction in the diameter of the pupil is resolved by the time point of 24 hours. PGF2a-l-ethanolamide causes a mild ocular surface hyperemia, compared to the rest for the vehicle, through the experimental period of 24 hours (Figure 15, Table 16). In the following Tables, unless otherwise indicated, the concentration of the test or control compounds is indicated by the logarithmic exponent only. In this way, and by way of example, "-8" in the Tables means a concentration of 10"8 M of the test or control substance.

Table 1. Effect of graded doses of PGF2a-l-ethanolamide on the smooth muscle of the isolated feline iris sphincter. The reference shrinkage is supplied by 10"7 M PGF2a, the values are means ± SEM, n = 4.

Table 2. Inhibitory effect of graduated doses of PGF2a 1-ethanolamide in a field-stimulated contraction of the guinea deferent vas deferens. The values are means ± SEM; n = 4 Table 3. Effect of graduated dose of PGF2a l-ethanolamide on the ileum of isolated chicks. The contraction of reference is supplied by 10"6 M PGE, the values are means of ± SEM, n = 4.

Table 4. Effects of graded doses of PGF2a-l-ethanolamide on ileus of isolated guinea pig. The reference shrinkage is provided by PGE2 10"6 M. the values are mean + SEM, n = 4.

Table 5. Effect of graded doses of PGF2a l-ethanolamide in isolated rat aorta. The reference shrinkage was provided by 10"7 M U-46619. The values are averages + SEM; n = 4 Table 6. Effect of graduated doses of prostaglandin F2a l-ethanolamide on platelet aggregation, on ADP-induced aggregation inhibition. The reference responses are provided by 2xl0"5 M ADP. The values are mean ± SEM, n = 4.

Table 7. Increase in the concentration of free intracellular Ca2 + [Ca2 +] i produced by graduated dose of prostaglandin F2a 1-ethanolaminda and prostaglandin F2a in human dermal fibroblasts CRL 1497. Values are mean ± SEM; n =.

Table 8. Vasorelation of the jugular vein segment of rabbit precontracted by prostaglandin F2a 1-ethanolamide and prostaglandin F2a. The reference vasorelaxation is provided by PGF2 10"7 M. Values are means ± SEM, n = 6 for PGF2a l-ethanolamide, n = 7 for Table 9. Increases in the free intracellular concentration of Ca + [Ca2 +] i produced by graduated dose of prostaglandin F2a l-ethanolamide and prostaglandin F2a in HEK-293, stably transfected in the FP receptor. Of recombinant feline. The values are means + SEM; n = 3 Table 10. Total accumulation of inositol phosphate, produced by graduated doses of prostaglandin F2a 1-ethanolamide and 17-phenyl prostaglandin F2a in HEK-293 cells stably transfected with the recombinant feline FP receptor. The reference stimulation was provided by 17-phenyl PGF2a 10"s M. the values are means ± SEM, n = 3 by PGF2a l-ethanolamide and 4 by 17-phenyl PGF2a from the experiments carried out in duplicate.

Table 11. Total accumulation of inositol phosphate produced by graduated dose of prostaglandin F2a 1-ethanolamide and 17-phenyl prostaglandin F2a in HEK-293 cells stably transfected with the recombinant human FP receptor. The reference stimulation is provided by 17-phenyl PGF2a 10"e M. the values are mean ± SEM, n = 3 for PGF2a l-ethanolamide and 4 for 17-phenyl PGFa from the experiments carried out in duplicate.

Table 12. Radioligand binding competence studies (PGF2a l-ethanolamide and 17-phenyl PGF2a Vs, 5nM 3H-17-phenyl PGF2a) in a recombinant feline FP receptor. The values are mean ± SEM; n = 3 of the experiments carried out in duplicate.

Table 13. Radioligand binding competence studies (PGF2a l-ethanolamide and 17-phenyl PGF2a Vs, 5nM 3H-17-phenyl PGF2a) in a recombinant human FP receptor. The values are mean ± SEM; n = 3 of the experiments carried out in duplicate.

Table 14. Effect of 0.1% prostaglandin F2a l-ethanolamide on the intraocular pressure of the dog. The values are mean ± SEM; n = 6 ** p < 0.01 important change of the Intraocular pressure in the baseline according to Student's t-test.

Table 15. Effect of 0.1% prostaglandin F2a 1-ethanolamide on the diameter of the dog's pupil. The values are ± SEM; n = 6 ** p < 0.01 important change in the pupil diameter of the baseline according to the Student's t test.

Table 16. Effects of 0.1% prostaglandin F2a 1-on hyperemia of the ocular surface of the dog. The values are ± SEM; n = 6. PHARMACEUTICAL COMPOSITIONS, METHODS OF USE Pharmaceutical compositions can be prepared by combining a therapeutically effective amount of at least one compound according to the present invention or a pharmaceutically acceptable salt thereof, as an active ingredient with ophthalmically excipient pharmaceutical excipients. conventional acceptable, and by the preparation of dosage unit forms suitable for topical ocular use. The therapeutically efficient amount is typically between about 0.0001 and about 5% (w / v), preferably about 0.001 to about 1.0% (w / v) in liquid formulations.

For ophthalmic application, the solutions are preferably prepared using a physiological saline solution as a main vehicle. The pH of such ophthalmic solutions should preferably be maintained at 6.5 and 7.2 with a suitable buffer system, preferred a substantially neutral pH. The formulations may also contain, pharmaceutically acceptable, conventional preservatives, stabilizers and surfactants. Preferred preservatives that can be used in the pharmaceutical compositions of the present invention, include but are not limited to benzalkonium chloride, chlorobutanol, thimerosal, phenyl mercuric acetate and phenyl mercuric nitrate. A preferred surfactant is for example, Tween 80. Similarly, various preferred carriers can be used in the ophthalmic preparations of the present invention. These vehicles include but are not limited to polyvinyl alcohol, povidone, hydroxypropylmethyl cellulose, poloxamer, carboxymethylcellulose, hydroxyethyl cellulose and purified water. Tonicity adjusters can be added as needed or convenient. They include but are not limited to salts, particularly sodium chloride, potassium chloride, mannitol and glycerin or any other suitable ophthalmically acceptable tonicity adjuster. Various buffers and means for adjusting the pH can be used as long as the resulting preparation is ophthalmically acceptable. In this way, the Buffer solutions include acetate buffer solution, citrate buffer solution, phosphate buffer solution and borate buffer solution. The acids or bases can be used to adjust the pH of these formulations as needed. In a similar line, an ophthalmically acceptable antioxidant for use in the present invention, includes but is not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Other components of the excipient that can be included in the ophthalmic preparations are the chelating agents. The preferred chelating agent is disodium edentate, although other chelating agents can also be used in place or in conjunction with it. The ingredients are usually used in the following amounts: Ingredient quantity (% w / v) Active ingredient around 0.001-5 Conservative 0-0.10 Vehicle 0-40 Tonicity adjuster 0-10 buffer solution 0.01-10 pH adjuster Q.s. pH 4.5-7.5 antioxidant as surfactant is needed as purified water is needed as needed to be 100% The actual dose of the active compounds of the present invention, depends on the specific compound and the condition to be treated, the selection of the appropriate dose is well within the knowledge of the technician enabled. The ophthalmic formulations of the present invention are conveniently packaged in suitable forms for a measured application, such as in containers equipped with a dropper to facilitate application to the eye. Suitable containers for drop-wise application are usually made of non-toxic, inert, suitable plastic material and generally contain between about 0.5 and about 15 ml of solution. Especially preservative-free solutions are often formulated in non-resealing containers containing up to about 10, preferably up to about 5 in unit dose, wherein a typical unit dose is from about 8 drops, preferably from 1 to about 3. drops. The volume of a drop is usually around 20-35 μl.

DETAILED DESCRIPTION OF THE SYNTHETIC PROCEDURES PGF2a (free carboxylic acid) To a solution of 20 g of PGF2a salt was added thrometinamine (51.9 mmol) in 150 ml H20, concentrated HCl such that the pH of the solution was adjusted to 2. The solution was extracted with 3 x 200 ml and concentrated in vacuo. The free carboxylic acid PGF2a appeared mainly as a solid layer between the aqueous and organic phases. The solid was collected from this layer and combined with solids obtained by filtration of the concentrated chloroform solution, and the combined solids were washed with 50% chloroform / methanol. Methyl ester of PGF2a; methyl (5Z, 8a, lio .. 13E, 15S) -9,11,15-trihydroxyprota-5,13-dien-1-oate. To a stirred solution of free carboxylic acid PGF2a (2.528 g, 7.13 mmol) in 50 ml of acetone, 3.2 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene (21.39 mmol) and 1.33 ml of iodomethane (21.39 mmol). The solution was stirred overnight, diluted with 150 ml ethyl acetate, washed with 2 x 50 ml 0.5 m LiOH, 1 x 50 ml brine and concentrated in vacuo to yield the title compound, methyl ester. pure (purity checked by ^ "H NMR) H1 NMR (CDC13): 5.56-5.34 (m, 4H), 4.01 (m, 1H), 3.87 (m, 1H), 3.78 (m, 1H), 3.63 (s) , 3H), 3.18 (t, 2H, J = 5.8 Hz), 2. 31-2.02 (m, 8H), 1.69-1.25 (m, 12H), 0.849 (t, 3H, J = 6.7 Hz). PGF2K l-ethanolamide; (52, 8a, 9a, lla, 13 E, 15S) -9, 11, 15-trihydroxy-N- (2-hydroxyethyl) prosta-5, 13-dien-1-amide was added to a stirred solution of sodium ester. methyl of PGF2a (235.4 mg, 0.639 mmol), in 4.5 ml of anhydrous methanol, 771 μl of ethanolamide (12.78 mmol). The tube containing the mixture was sealed and heated at 50 ° C overnight. An aliquot was taken, concentrated in high vacuum with heat to remove the excess ethanolamine and analyzed by "" H NMR The reaction was indicated to be 80% complete.The solution was concentrated under high vacuum 65 ° C. 1.5 hours, then at 60 ° C overnight by a Kugehlrohr distillation to remove residual ethanolamine.1H NMR and 5% TLC in methanol / ethyl acetate indicates the separation of ethanolamine. (Methyl ester Rf = 0.41 , PGF2a-l-ethanolamide Rf = 0.04) The crude material was flash chromatographed with 5% ethanol / ethyl ecetate to recover the remaining unreacted starting material, methyl ester in reactions 4-8 and 50% and in methanol / ethyl acetate to yield the desired title compound in fractions 11-18, Additional flash chromatography of fractions 11-18 with 15% methanol / ethyl acetate, produced the free titer compound of the starting material, but still contaminated with the C15 epimer in some fractions (in fractions 7-10), and the desired product in the pure state (in fractions 11-20). The "" H + 13 C NMR spectra of the title compound and its C 15 epimer are identical Theoretical yield = 254.0 mg, actual yield obtained = 205.6 mg, 81% H1 NMR (CD30D): 5.4-5.2 (m, 4H ), 3.98 (m, 1H), 3.89 (m, 1H), 3.72 (m, 1H), 3.47 (t, 2H, J = 5.8 Hz), 3.18 (t, 2H, J = 5.8 Hz), 2.24 - 1.90 (m, 8H), 1.50 - 1.21 (m, 12H), 0.796 (t, 3H, J = 6.5 Hz) It is noted that in relation to this date, the best method known to the applicant to carry out the cited invention, is that which is clear from the present description of the invention.

Claims (34)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula characterized in that dotted lines represent the absence of a link, or a link with the condition that there are no two adjacent double bonds in the formula; the attached wavy lines represent either an alpha (a, below) or a beta (ß, above) configuration, where the wavy lines are attached to double bonds that represent either a Z (cis) or E (trans) configuration; shaded lines indicate an alpha (a) configuration and solid triangles indicate a beta (ß) configuration; m is an integer that has values from 0 to 5; n is an integer having the values 1-6, with the proviso that the compound represented by the formula is not PGF 2a l-ethanolamide; q and r each independently, are integers that have the value of 0 to 6; X is CH2 / O or S, with the proviso that when X is 0 or S, then dotted lines adjacent to X represent the absence of a link; R is CH 3, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons or phenyl, furyl or thienyl, substituted by itself with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons , N02, CN, COOH and COO alkyl, where alkyl has from 1 to 6 carbons; Ri, R2, R3, and R each independently represent H, a straight or branched chain alkanoyl group having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons; R5 is H or a straight or branched chain alkyl group having 1 to 6 carbons, and R6 is H or a straight or branched chain alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of the compound, and the compounds are active to reduce intraocular pressure in the eye of a mammal, but do not exert their ocular hypotensive activity through the prostaglandin FP receptor.
2. 2. The compound according to claim 1, characterized in that it has the formula
3. 3. The compound according to claim 2, characterized in that the dashed lines between the carbons 10 and 11, 8 and 12, and 17 and 18, represent the absence of a bond, and between the carbons 5 and 6 represent a bond.
4. 4. The compound according to claim 2, characterized in that R5 is H or lower alkyl of 1 to 3 carbons.
5. 5. The compound according to claim 4, characterized in that R5 is H.
6. The compound according to claim 2, characterized in that R6 is H or lower alkyl of 1 to 3 carbons.
7. 7. The compound according to claim 6, characterized in that R6 is H.
8. 8. The compound according to claim 2, characterized in that n is 2.
9. 9. The compound according to claim 2, characterized in that the configuration of the groups 0RX, 0R2 and 0R3 is alpha, the dotted line between positions 5 and 6 represents a link and the configuration of the double bond 5-6 is 2 (cis).
10. 10. A compound of the formula characterized in that Rl t R2, R3, and R4 each independently represents H, a straight or branched chain alkanoyl group, having 1 to 6 carbons, benzoyl or straight or branched chain alkyl having from 1 to 6 carbons; n is an integer that has the values 1 to 6; the compounds are active to reduce intraocular pressure in the eye of a mammal, but do not exert their ocular hypotensive activity through the prostaglandin FP receptor, with the proviso that when n is 2, then at least one of the Rl groups R2, R3, and R4 is not H.
11. 11. A substantially pure, isolated chemical substance, characterized in that it has the formula:
12. 12. An effective pharmaceutical composition for reducing intraocular pressure in the eye of a mammal in need of treatment by such a composition, the composition characterized in that it comprises as its active ingredient an effective amount of one or more compounds of the formula, where dotted lines represent the absence of a link, or a link with the condition that there are no two adjacent double bonds in the formula, - the attached wavy lines represent either an alpha (a, below) or a beta (ß) configuration , above), where the wavy lines are attached to double bonds that represent either a Z (cis) or E (trans) configuration; shaded lines indicate an alpha (a) configuration and solid triangles indicate a beta (ß) configuration; m is an integer that has values from 0 to 5; n is an integer that has the values 1-6; q and r each independently, are integers that have the value of 0 to 6; X is CH2, O or S, with the proviso that when X is O or S, then the dotted lines adjacent to X represent the absence of a link; R is CH 3, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons or phenyl, furyl or thienyl, substituted by itself with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons , N02, CN, COOH and COO alkyl, where alkyl has from 1 to 6 carbons; Ri, R2, R3, and R4 each independently represent H, a straight or branched chain alkanoyl group having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons; R5 is H or a straight or branched chain alkyl group having 1 to 6 carbons, and R6 is H or a straight or branched chain alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of the compound, and the compounds are active to reduce intraocular pressure in the eye of a mammal, but do not exert their ocular hypotensive activity through of the prostaglandin FP receptor, and a pharmaceutically acceptable excipient.
13. 13. The pharmaceutical composition according to claim 12, characterized in that the active compound has the formula
14. 14. The pharmaceutical composition according to claim 13, characterized in that in the formula of the active compound, the dashed lines between the carbons 10 and 11, 8 and 12, and 17 and 18, represent the absence of a bond, and between the carbons 5 and 6 represent a link.
15. 15. The pharmaceutical composition according to claim 13, characterized in that in the formula of the active compound, R5 is H or lower alkyl of 1 to 3 carbons.
16. 16. The pharmaceutical composition according to claim 15, characterized in that in the formula of the active compound, R5 is H.
17. 17. The pharmaceutical composition according to claim 13, characterized in that in the formula of the active compound, R6 is H or lower alkyl of 1 to 3 carbons.
18. 18. The pharmaceutical composition according to claim 17, characterized in that in the formula of the active compound, R6 is H.
19. 19. The pharmaceutical composition according to claim 13, characterized in that in the formula of the active compound, n is 2.
20. The pharmaceutical composition according to claim 13, characterized in that in the formula of the active compound, the configuration of the groups ORa., 0R2 and 0R3 is alpha, the dotted line between positions 5 and 6 represents a link and the configuration of the double bond 5-6 is Z (cis).
21. 21. The pharmaceutical composition according to claim 13, characterized in that the active compound has the formula
22. 22. The pharmaceutical composition according to claim 21, characterized in that the active compound has the formula
23. 23. The pharmaceutical composition according to claim 12, characterized in that it is adapted for topical administration to the eye of the mammal.
24. 24. The pharmaceutical composition according to claim 13, characterized in that it is adapted for topical administration to the eye of the mammal.
25. 25. The pharmaceutical composition according to claim 21, characterized in that it is adapted for topical administration to the eye of the mammal.
26. 26. The pharmaceutical composition according to claim 22, characterized in that it is adapted for topical administration to the eye of the mammal.
27. 27. A method for reducing infraocular pressure in the eye of a mammal in need of such treatment, the method characterized in that it comprises the step of administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable excipient and as its active ingredient, an effective amount of one or more compounds of the formula, wherein dotted lines represent the absence of a link, or a link with the condition that there are no two adjacent double bonds in the formula; the attached wavy lines represent either an alpha (a, below) or a beta (ß, above) configuration, where the wavy lines are attached to double bonds that represent either a Z (cis) or E (trans) configuration; shaded lines indicate an alpha (a) configuration and solid triangles indicate a beta (ß) configuration; m is an integer that has values from 0 to 5; n is an integer that has the values 1-6; q and r each independently, are integers that have the value of 0 to 6; X is CH2, 0 or S, with the proviso that when X is 0 u S, then dotted lines adjacent to X represent the absence of a link; R is CH 3, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons or phenyl, furyl or thienyl, substituted by itself with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons , N02, CN, COOH and COO alkyl, where alkyl has from 1 to 6 carbons; Ri, R2, R3, and R4 each independently represent H, a straight or branched chain alkanoyl group having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons; R5 is H or a straight or branched chain alkyl group having 1 to 6 carbons, and R6 is H or a straight or branched chain alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of the compound, and the compounds are active to reduce intraocular pressure in the eye of a mammal, but do not exert their ocular hypotensive activity through the prostaglandin FP receptor.
28. 28. The treatment method according to claim 27, characterized in that the active compound has the formula
29. 29. The treatment method according to claim 28, characterized in that the active compound has the formula
30. 30. The method according to claim 29, characterized in that the active compound has the formula
31. 31. The method of treatment according to claim 27, characterized in that the pharmaceutical composition is adapted for topical administration to the eye, and the method comprises administering the composition topically to the eye of the mammal.
32. 32. The method of treatment according to claim 28, characterized in that the pharmaceutical composition is adapted for topical administration to the eye, and the method comprises administering the composition topically to the eye of the mammal.
33. 33. The method of treatment according to claim 29, characterized in that the pharmaceutical composition is adapted for topical administration to the eye, and the method comprises administering the composition topically to the eye of the mammal.
34. 34. The treatment method according to claim 30, characterized in that the pharmaceutical composition is adapted for topical administration to the eye, and the method comprises administering the composition topically to the eye of the mammal.